Process for the production of steroid bromohydrins or cyclic ethers derived therefrom



.Derek Harold Richard Barton, London, England, assignor i steroid bromohydrin containing the grouping with free bromine radicals. The 'bromohydrin may be United States Patent Ofifice 3,354,150 Patented Nov. 21, 1 967 PRocEss FOR THE PRohUcTroN F STEROID BROMOHYDRINS 0R CYCLIC ETHERS DE- RIVED THEREFROM to Research Institute for Medicine and Chemistry, Inc., Cambridge, Mass., a corporation of Massachusetts No Drawing. Filed May 10, 1965, Ser. No. 454,742

Claims priority, application Gaeat Britain, May 15, 1964,

Claims. for. 260-23955) 7 ABSTRACT OF THE DISCLOSURE is produced by reacting a nitrite ester of a steroid alconverted into a cyclic ether, either spontaneously or by treatment with a base.

This invention relates to a novel process for the production of b.omohydrins and cyclic ethers derived therefrom.

In synthetic organic chemistry it is often required to introduce a cyclic ether grouping into a molecule, especially in the field of steroid or alkaloid synthesis. It is also useful to provide various types of bromohydrins in which the bromine atom and hydroxyl group are either 'conformationally adjacent or are able to become conformationally adjacent, since these can usually be converted into the desired cyclic ethers by removal of HBr 40 or the bromine atom may be replaced by other substituents such as ether, thioether, amino groups, etc.

By the term conformationally adjacent atoms or groups is meant that these are so positioned that they may approach without appreciable molecular strain to within the distance normal for an interatomic bond. Thus, for example, in the steroids, a hydroxyl group in the 6,8-position is conformationally adjacent to'a hydrogen at the 19-position while a hydroxyl in the lfl-position' is conformationally adjacent .to a hydrogen at the 115- position.

It will be seen that in the above examples the conformationally adjacent atoms or groups are separated by a chain of four intervening carbon atoms, thereby allowing the conformationally adjacent atoms or groups to form part of a six-membered structure which, as is wellknown, is normally substantially free from strain. Naturally, Where the intervening carbon atoms form part of a structure in which the bond rotation and movement is restricted, as in polycyclic structures such as steroids, the arrangement of all the bonds must allow the relevant atoms or groups to become adjacent.

It has been observed previously that when alcohols possessing a hydroxyl group conformationally adjacent to a hydrogen atom are reacted with iodine and lead tetraacetate, an oxide bridge is often formed between the carbon atoms carrying the said hydrogen and. hy-

droxyl groups to produce a cyclic ether. It has also been suggested that a similar effect could be achieved by reacting the alcohol with a tertiary butyl hypohalite or with interhalogen compounds, cyanogen halides, N-halogenoamides, imides, etc.

In US. application No. 349,478, filed Mar. 4, 1964, and now Patent No. 3,290,296, there is described a process for the preparation of cyclic ethers or of iodohydrins having a conformationally adjacent iodine atom and hydroxyl group, wherein an alcohol possessing a carbonattached hydrogen atom which is or is able to be conformationally adjacent to the alcoholic hydroxyl group is reacted with iodine and a hypochlorite, hypobromite or nitrite ester of a tertiary alcohol or is converted into a nitrite ester and reacted with iodine, whereby the said hydrogen atom is replaced by an iodine atom to form an iodohydrin which may be converted into a cyclic ether by elimination of hydrogen iodide.

It has now been found that it is possible to form bromohydrins rather than iodohydrins by reaction of a nitrite ester of an alcohol having a hydrogen atom conformationally adjacent to the hydroxyl group with a substance liberating free bromine radicals, for example molecular bromine, an N-bromoamide or imide, cyanogen bromide, etc., or, more especially, bromo-trichloromethane. Such bromohydrins readily dehydrobrominate to form cyclic ethers, often spontaneously.

According to the present invention, therefore, there is provided a process for the preparation of bromo-hydrins having a bromine atom conformationally adjacent to or able to become conformationally adjacent to a hydroxyl group or cyclic ethers derived therefrom wherein a nitrite ester of an alcohol possessing a carbon-attached hydrogen atom which is or is able to be conformationally adjacent to the alcoholic hydroxyl group is reacted with, a substance liberating free bromine radicals, whereby the said carbon-attached hydrogen atom is replaced by a bromine atom to form a bromo-hydrin which may be converted into a cyclic ether by elimination of hydrogen romide. g

The new process according to the invention is thus able to introduce a bromine atom at a previously unsubstituted carbon atom and allows cyclic ethers to be prepared without requiring both the oxygen-linked carbon atoms to be substituted previously. The use of the alcohol in the form of its nitrite ester has the advantage that sensitive groupings, such as keto groups, present in the molecule need not be protected.

The reaction is effected by generation of free bromin radicals and the reaction conditions will depend on the nature of the bromine-containing reactant. In general, it is preferred that the reaction be carried out under ultraviolet radiation since this promotes liberation of free bromine radicals and also the reaction of the nitrite ester. Thus, for example, bromo-trichloromethane liberates bromine radicals on photolysis and where this compound is used, the reaction mixture may be irradiated with ultraviolet light of the wave-lengths causing the splitting of the carbonromine and nitrite bonds. In general, the

0 wavelength of the ultraviolet light will be in the range 240 to 500 m and thus, for example, a mercury vapour lamp may be used as light source for such a photolysis. The reaction is preferably carried out in an inert solvent medium and in photolytic reactions the solvent chosen will be one which dissolves the reactants and does not significantly absorb radiation of the photolytic wavelength. Thus,. for example, chlorinated hydrocarbon solvents such as carbon tetrachloride or hydrocarbon solvents such as benzene, toluene, etc. are useful in steroid synthesis since they dissolve many steroids and are not substantially opaque to the required radiation.

6,19-ethers by the present process and then converted to 3-ketones and caused to undergo [3-Cli111i113ti0n to yield 4,5-dehydro-3-keto-steroid 6,19-xides'. These may then be reductively cleaved with dissolving metal or low va- The bromohydrin may be converted into the rlelency metal ion reducing agents, e.g. zinc and acetic acid, sponding cyclic ether by treatment with a base, e.g. an chromous chloride, aluminium amalgam etc. to yield 4,5- alkali or alkaline earth metal hydroxide, carbonate, etc, d hydro-3-keto-l9-hydroxy steroids such as 19-hydroxy an Organic nitrogen base Such as triethylamine, progesterone which is physiologically active as aprogestamethylamine, pyridine, etc. One especially useful medium tional agent. Conversion to the 3-ketone may be effected for idehydfobmmination i5 Potassium of Sodium Y by mineral acid hydrolysis in the case of the ketals and ide in solution in an alkanol such as methanol or ethanol, hi k i d i h case of 3-acy1QXy groups by min ral at about 5% concentration acid hydrolysis followed by oxidation with a reagent serv- In the general case it is not necessary for all the atoms ing to oxidise an alcohol to a ketone, for example chromiintervening between the conformationally adjacent groups urn trioxide, e.g. in acetone. B-Elimination may be efiectof the alcohol reactant to be carbon and in general it is ed under acid conditions and may take place spontaneouspossible for at least one intervening atom to be oxygen, ly during oxidation. Preferred groups in other positions nitrogen p Provided that the p d is C in the steroid molecule include a fluorine, chlorine or cally stable and that the atoms carrying the conformabromine atom in the 9-position, a protected or unprotecttionally adjacent atoms or groups are both carbon. The ed keto group in the ll-position, a protected or unproprocess of the invention is thus of particular use in contected keto, acyloxy, acetyl, ,B-acetyl-a-acyloxy or octyl verting compounds having the grouping group at the 17-position and/or an alkyl group in the 2-, 6- or 1.6-position. Other conformationally adjacent positions in the steroid I l molecule include the 11- and 18-positions and the ZO- and lnto bromohydrins having the grouping 18 p0SitionS l I l The nitrite ester of the alcohol to be iodinated or T cyclised may be prepared, for example, by the methods 0 th th r t th conventional in the art, for example by reaction with a r 6 cy w e e 5 con ammg e groupmg nitrosylating agent such as a nitrosyl halide, e.g. nitrosyl l chloride or bromide.

i In order that the invention may be well understood We 7 glve the following examples by way of illustration only.

I; All temperatures are in C. which ma be formed therefrom, X being a methylene, Example 1-Ph0t0l}SiS f fl' y 5- methylidene, methylidyne or ,imino group or an oxygen, nitrite with b"Omotrichloromethane nitrogen or sulphur atom.

As indicated above, the reaction is especially useful in Method-TO above mmte mmole) m benzene steroid synthesis and one particular application is the s was added the aPPYQPYIaFe amount f bromo' preparation vof 6719631615- from 6 hydroxy steroids. 40 trichloromethane and the solution irradiated with a 2Q0 By the term steroids we mean compounds having the watt lamp using a Pyrex filter 'f q cxtemany 1 m basic cyclopentanoperhydrophenanthrene ring structure an lce'wafer bath Ajiter lrr'adlanon the solutlon was and which may contain various substituents and/ or double Washed wlth dned (Na2SO4 filtered and evapo' bonds, e.g. a keto, hydroxy or acyloxy grou i h rated to dryness in vacuo. The residual gum was heated position, alkyl gmups i and l6 positions keto, 1n refluxing 5% methanohc potassiumecetate solution for ace yl g oup etc. at the 20-p0sition, keto groups, hydroxy four hours before again extracting with methylene chloa d/ hydrocarbon of acyl (gig t t l) groups ride and drying. On evaporation, the residue was chroetc. at the 17-position, a hydroxy or keto group at the 11- matogfaphed through acid Washed alumina using or 12 1 1 a h d group at the @Position, a benzene and methylene chloride mixtures to elute. Gendroxy group t h fgp i i a double bond at the 1- erally, the nature of the reaction mixture and the chroancl/or 4 position, a halogen .atom such .as fluorine in the matogfaphic fwd-i995 were lexamifled y thin'layel' 11- -or 6-position etc. matography.

Steroid 6,19-ethers may be converted by reduction to Results:

TABLE .1

Equivalents 01 Percent Percent Percent Run Bromo- -01 6-one 6,19 ether Comments trichloromethane 47 10 18 1 Trace I 23 Reerystallized. 47 50 17 Trace. 38 Do. 69 50 20. 5. 35 Do. 75 w 50 7 l 45 Ether only Recrystallized+ NEt3 (4 equivalents).

1 Carried out for 30-40 minutes.

Example 2.-Ph0t0lysis 0 predm'solone bismethylen edi oxide-1 Iii-nitrite with brom otrichloromethane Method.The photolysis was elfected as in Example 1. Cyclisation of bromohydrin was carried out with a 5% methanolic solution of potassium hydroxide for one hour at reflux. Chromatography was on alumina (loading of ca. 40); elution was with methanolic-methylene chloride 7 mixtures.

TABLE 2 Run Equiva- Photolysis Percent Percent Percent Remarks lents (IV) Time ll-one 11,18

ether 11 2% hrs 6 l0. 5 12 Not recrystallized. 100 1% hrs- 5 8 6 24 40 min. 11. 2 12. 7 Recrystallized.

Example 3.Androsta-L4-dien-3J7-dione-1I,18-0xide Example 4.1S-bromo-androsta-I,4-dien 3,11,17-trine Androsta-1,4-dien-3,17-dion-1 lfi-yl-nitrite (0.365 gm.) in benzene (75 ml.) and bromotrichloro-methane (6.0 gm.) were irradiated as in Example 3. The solvents were removed in vacuo. The crude product in acetone (15 ml.) was treated with Jones reagent (1.0 mL, 2 N). After 6 min. at room temperature the mixture was worked up as in Example 1. Chromatography on alumina (15 gm.) gave the desired bromo compound (78 mg.), M.P. 183- 6 (dec.), a +212,

mg 239 m (e=17,200)

Analysis.-Calcd. for C H BrO C, 60.58; H, 5.61; O, 12.72. Found: C, 60.72; H, 5.57; O, 12.54.

Example 5.18-br0mo-prednisone acetate Prednisolone acetate-1 lp-yl-nitrite (3.0 gm.) in benzene (160 ml.) and bromotrichloro-methane (26 gm.) was irradiated as in Example 3. The solvents were removed in vacuo. The crude product was dissolved in acetone (60 ml.) and treated with Jones reagent ml., 2 N) for 6 min. at room temperature. After working up as in Example 1, the desired product was isolated by chromatography on alumina (60 gm.) to give 0.358 gm., M.P. 1725 (dec.), a +179,

A 239 mu (e=16,300)

Analysis.Calcd. for C H BrO C, 57.61; H, 5.07; O, 20.02%. Found: C, 57.83; H, 5.75; O, 20.10%.

Example 6.-Use of Br as source of bromine atoms (65,19-0xid0-ch0lestan0l acetate) I claim: 1. A process for the preparation of a steroid bromohydrin containing the grouping or upon elimination of hydrogen bromide, a steroid compound containing the grouping comprising reacting a nitrite ester of a steroid alcohol containing the grouping with free bromine radicals.

2. A process as claimed in claim 1 in which the free bromine radicals are furnished by cyanogen bromide, trichlorobromo methane, bromine, an N-bromoamide or an N-bromo-imide.

3. A process as claimed in claim 1 in which the reaction mixture is irradiated With ultraviolet radiation in the range 240500 mg.

4. A process as claimed in claim 3 in which the reaction mixture is irradiated with radiation from a mercury vapour lamp.

5. A process as claimed in claim 1 in which the reaction is eifected in an inert solvent medium.

6. A process as claimed in claim 5 in which the solvent is a hydrocarbon or chlorinated hydrocarbon solvent.

7. A process as claimed in claim 6 in which the solvent is carbon tetrachloride, benzene or toluene.

8. A process as claimed in claim 1 in which a steroid bromohydrin is produced and dehydrobrornination is effected by treatment of the bromohydrin reaction product with a hydroxide or carbonate of an alkali metal or al kaline earth metal or an organic nitrogen base.

9. A process as claimed in claim 8 in which the dehydrobromination is effected with sodium or potassium hydroxide in alkanolic solution.

10. A process as claimed in claim 1 in which the ester is a nitrite ester of a 6fl-hydroxy or llfl-hydroxy steroid.

References Cited UNITED STATES PATENTS 3,290,296 12/1966 Barton 260--239.55

ELBERT L. ROBERTS, Primary Examiner. HENRY FRENCH, Examiner, 

1. A PROCESS FOR THE PREPARATION OF STEROID BROMOHYDRIN CONTAINING THE GROUPING 